Herpes simplex virus (HSV) is a common and significant human pathogen that causes a range of diseases, from cold sores and genital lesions to blindness and fatal encephalitis. Latent infection is life-long, and despite much effort there is no effective HSV vaccine. Little is known about the molecular underpinnings of HSV?s tropism for epithelial cells, the primary portal of entry into the human host. In our model of HSV entry, the virus utilizes a low pH, endocytic pathway for infection of epithelial cells and several other cell types, and a pH-independent pathway in neurons. An emerging concept in herpesvirology is that endosomal pH of the host cell is required for viral entry, often in a cell tpe specific manner. Envelope glycoproteins B, (gB), gD, and gH/gL are necessary for HSV entry into all cell types, regardless of which pathway is supported. Importantly, viral envelope proteins specifically responsible for HSV?s tropism for epithelial cells, but not neurons, remain to be identified. Mildly acidic pH changes the conformation of the HSV fusion protein gB, but the precise role that pH plays in herpesviral entry is not clear. HSV gK is a polytopic envelope glycoprotein that plays roles in viral fusion, assembly, and egress. Our overall hypothesis is that HSV gK is specifically required for viral entry into cells that support a low pH entry pathway, such as human epithelial cells. For this pilot study on the role of gK in HSV entry, two specific aims are proposed. In Specific Aim # 1 we will determine the role of HSV-1 gK in viral entry into human epithelial cells. For Specific Aim # 2, we will ascertain the effect of HSV-1 gK on conformational changes in gB. A combination of molecular, biochemical, and cell biological approaches will be used to reach these goals. Achieving the stated aims will reveal significant new information about herpesviral entry, and will aid potentially in the development of new vaccine candidates and anti-viral therapeutics.